Late-onset lethal complication of non-surgically managed massive gastric conduit necrosis after esophagectomy: a case report.

BACKGROUND: Gastric conduit necrosis (GCN) after esophagectomy is a serious complication that can prove fatal. Herein, we report a rare case of GCN with a severe course that improved with conservative treatment. CASE PRESENTATION: We present the case of a 78-year-old male patient who underwent an Ivor Lewis esophagectomy and developed a massive GCN. The patient was critically ill in the initial phase but recovered quickly; he also had a ruptured gallbladder and a bleeding jejunal ulcer. On the 22nd postoperative day, massive GCN was revealed on endoscopy. Considering the recovery course, careful observation with a decompressing nasal gastric tube was the treatment of choice. The GCN was managed successfully, having been completely replaced by fine mucosa within 9 months postoperatively. The patient completed his follow-up visit 5 years after surgery without any evident disease recurrence. Five and a half years after the surgery, the patient presented with progressive weakness and deterioration of renal function. Gastrointestinal endoscopy revealed a large ulcer at the anastomotic site. Three months later, computed tomography revealed a markedly thin esophageal wall, accompanied by adjacent lung consolidation. An esophagopulmonary fistula was diagnosed; surgery was not considered, owing to the patient's age and markedly deteriorating performance status. He died 2013 days after the diagnosis. CONCLUSIONS: Massive GCN after esophagectomy often requires emergency surgery to remove the necrotic conduit. However, this report suggests that a conservative approach can save lives and preserve the gastric conduit in these cases, thereby augmenting the quality of life.

Risk Factors for Lymph Node Metastasis and Recurrence in T1 Colorectal Cancer: Analysis of 801 Patients in a Single Institute.

OBJECTIVE: To identify risk factors for lymph node metastasis and postoperative recurrence of pT1 colorectal cancer by clinicopathological study of surgically resected cases. METHODS: In 801 patients with pT1 colorectal cancer who underwent surgical resection with lymph node dissection between April 2007 and January 2021, we evaluated clinicopathological factors (age, gender, BMI, serum CEA level, tumor localization, additional resection after endoscopic treatment, operation time, blood loss, histological type, tumor size, vascular invasion, and central lymph node dissection). We performed univariate and multivariate analyses to examine risk factors for lymph node metastasis. We also examined risk factors for recurrence in 583 patients up to December 2017. RESULTS: Lymph node metastasis was observed in 100/801 patients (12.5%). Multivariate analysis of lymph node metastasis showed that patients with positive lymphatic invasion (odds ratio 2.57, 95% CI 1.62-4.04, P < .0001), positive venous invasion (odds ratio 2.31, 95% CI 1.48-3.61, P = .0002), and histologically poorly differentiated type (odds ratio 4.54, 95% CI 1.35-15.2, P = .014) were identified as risk factors. Postoperative recurrence was observed in 18/580 patients (3.1%). Risk factors for postoperative recurrence were also examined, including preoperative endoscopic treatment (odds ratio 3.59, 95% CI 1.18-10.9, P = .024), positive venous invasion (odds ratio 3.63, 95% CI 1.22-10.8, P = .021), positive lymph node metastasis (odds ratio 4.91, 95% CI 1.10-21.8, P = .037) were extracted as risk factors. DISCUSSION: In this study, venous invasion, lymphatic invasion, and histologically poorly differentiated type were identified as risk factors for lymph node metastasis in T1 colorectal cancer, and positive venous invasion, positive lymph node metastasis, and preoperative endoscopic treatment were identified as risk factors for recurrence. We hope that large prospective study will lead to the development of a more specific treatment strategy, including endoscopic treatment and additional surgical resection.

Short-term results of robot-assisted colorectal cancer surgery using Senhance Digital Laparoscopy System.

BACKGROUND: The Senhance Digital Laparoscopy System (Asensus Surgical Inc, Morrisville, NC, United States), which was introduced for the first time in Japan by our hospital, is a new surgical assistive robot following the da Vinci Surgical System. We herein report the short-term outcomes of 55 colorectal cancer surgery cases using this system at our hospital to assess the feasibility and safety of our procedures. MATERIALS AND METHODS: We retrospectively reviewed the patient backgrounds and surgical outcomes of 55 patients who underwent Senhance-assisted laparoscopic colorectal cancer surgery. RESULTS: The median age was 71 years. There were 31 males and 24 females, and the median body mass index was 23.1 kg/m2 . Fifteen patients had a history of abdominal surgery. The most common surgical technique was ileocecal resection (18 cases, 32.7%), followed by high anterior resection (11 cases, 20.0%). D2 or D3 dissection was performed in each operation, and D3 dissection was performed in 41 cases (74.5%). The median operative time was 240 minutes, the median blood loss was 5 mL, there were no intraoperative complications, and there were no cases of intraoperative blood transfusion. The median postoperative hospital stay was 7 days, which was comparable to conventional laparoscopic surgery. Postoperative complications of grade 2 or higher in the Clavien-Dindo classification were observed in two cases. CONCLUSION: The short-term results of 55 colorectal cancer surgery cases using the Senhance Digital Laparoscopy System were excellent and the system was introduced and surgery was safely performed.

The first single-incision plus one-port transverse colon resection using Senhance Digital Laparoscopy System: a case report.

BACKGROUND: We have introduced the Senhance Digital Laparoscopy System and actively use for colorectal cancer surgery. Recently, we also try to perform surgery by reduce port as less invasive method. For the first time, we report a case of single-incision plus one-port transverse colectomy using Senhance system. CASE PRESENTATION: The case was a 57-year-old woman, diagnosed with transverse colon cancer referred to our department. The preoperative diagnosis was cT1bN0M0, Stage I. We performed single-incision plus one-port transverse colon resection using Senhance system without any problems. The operative time was 203 min and the blood loss was 35 ml. CONCLUSION: We report the first case of single-incision plus one-port transverse colectomy using Senhance system. We trust this approach will find increasing use, enabling a safer means of minimally invasive robotic surgery.

Impact of Lymphovascular Invasion in Patients With Stage II Colorectal Cancer: A Propensity Score-matched Study.

BACKGROUND/AIM: Whether lymphovascular invasion (LVI) is a high-degree risk factor in stage II colorectal cancer has not been fully clarified, as different results have been reported in the literature. If LVI is a risk factor, postoperative chemotherapy may be recommended. The purpose of this study was to evaluate the impact of lymphovascular invasion on disease recurrence and patient prognosis in conjunction with stage II colorectal cancer (CRC). PATIENTS AND METHODS: A total of 636 patients with stage II CRC, each undergoing radical resection between April 2007 and December 2015, were selected for the study. Subjects with or without venous or lymphatic invasion were assigned to positive and negative groups, respectively. We then compared overall survival (OS) and disease-free survival (DFS) using propensity score matching. RESULTS: After matching (n=226, each group), OS and DFS were found to be significantly lower (OS: p=0.047; DFS: p=0.004) in patients positive (vs. negative) for venous invasion. However, the same was not true of lymphatic invasion. After matching, positive and negative groups (n=92, each) did not significantly differ in terms of OS (p=0.951) or DFS (p=0.258). CONCLUSION: In patients with stage II CRC, venous invasion proved to be a significant high-degree risk factor that may warrant adjuvant chemotherapy.

Prognostic Utility of Geriatric Nutritional Risk Index After Curative Resection of Colorectal Cancer: A Propensity Score-matched Study.

Background/Aim: The geriatric nutrition risk index (GNRI) is a presumptive prognosticator in a variety of carcinomas. We investigated whether it similarly predicts outcomes of elderly patients with colorectal cancer (CRC). Patients and Methods: A total of 904 older adults (≥65 years) undergoing radical resections of CRC between April 2011 and December 2015 proved eligible for study. Each was grouped by preoperative status (cut-off point, 98) as low-level or normal GNRI, using propensity score matching to compare rates of complications, disease-free survival (DFS), and overall survival (OS). Results: After matching (n=127, each group), those with low-level (vs. normal) GNRI values experienced significantly more complications (p=0.001), and 5-year survival was significantly poorer (DFS: p=0.006; OS: p=0.002). Conclusion: In elderly patients with resected CRC, preoperative GNRI may have significant prognostic merit.

A long-term survivor of clear cell sarcoma-like tumor of the gastrointestinal tract with liver metastasis: a case report.

BACKGROUND: Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLTGT) is extremely rare. It is a mesenchymal neoplasm that usually forms in the small intestine of adolescents and young adults, is prone to local recurrence and metastasis, and has a high mortality rate. We report a patient with CCSLTGT with lymph node- and liver metastases, who continues to survive 6 years after initial surgical resection. CASE PRESENTATION: A 38-year-old woman presented with lightheadedness. Laboratory analysis revealed anemia (hemoglobin, 6.7 g/dL), and enhanced computed tomography (CT) demonstrated a mass in the small intestine, about 6 cm in diameter, with swelling of 2 regional lymph nodes. Double-balloon small intestine endoscopic examination revealed a tumor accompanied by an ulcer; the biopsy findings suggested a primary cancer of the small intestine. She was admitted, and we then performed a laparotomy for partial resection of the small intestine with lymph node dissection. Pathologic examination revealed CCSLTGT with regional lymph node metastases. About 3 years later, follow-up CT revealed a single liver metastasis. Consequently, she underwent a laparoscopic partial liver resection. Histopathologic examination confirmed that the liver metastasis was consistent with CCSLTGT. It has now been 3 years without a recurrence. CONCLUSION: Repeated radical surgical resection with close follow-up may be the only way to achieve long-term survival in patients with CCLSTGT.

Right hemicolectomy with D3 lymph node dissection for right-sided transverse colon cancer using the Senhance robotic system: a case report.

BACKGROUND: The evolution of remote systems and artificial intelligence technology has led to increase in robotic surgeries. One system used in this case report is the Senhance robotic system. The most important premise for using robotic surgery in cancer therapeutics is to ensure oncological safety. Similar to conventional laparoscopic surgery, robotic surgery needs to be a reliable and secure surgical procedure, such as complete mesocolic excisions with central vascular ligations in Western countries or D3 lymph node dissections (dissection of the lymph nodes that locates from the origin to the terminal branch of the main feeding artery of cancer) in Japan. CASE PRESENTATION: A 76-year-old man underwent clinical examination for severe anemia. He was diagnosed with transverse colon cancer of tumor (T)3, node (N)1a, metastasis (M)0 cancer stage IIIA. A right hemicolectomy with D3 lymph node dissection using the Senhance surgical system was performed. The operative time was 313 min and the estimated blood loss was 5 ml. He was discharged from our hospital 12 days after the surgery without any complications. What is the remarkable of this report, not only mobilization of right colon but also D3 lymph node dissection and vascular ligation were performed intraperitoneally by using Senhance robotic system as conventional laparoscopic surgery. We tried using fourth robotic arm to accomplish lymphadenectomies and middle colic artery dissection. A right hemicolectomy with D3 dissection using the Da Vinci surgical system was reported. Another report of a right hemicolectomy performed with the Senhance robotic system was identified; however, in that study, lymph node dissections were not performed intraperitoneally. CONCLUSIONS: Therefore, to our knowledge, this is the first report using the Senhance robotic system for right hemicolectomy with D3 dissection. We hope that our case report will assist in the establishment of this robotic procedure in surgical practice.

Laparoscopic right hemicolectomy for metastatic renal cell carcinoma in the ascending colon: A case report.

INTRODUCTION: Renal cell carcinoma (RCC) arises from the renal parenchyma and is the most common primary malignancy of the kidney. RCC frequently metastasizes to the lung, bone, lymph nodes, and other locations, but rarely to the colon. We report a case of metastatic RCC of the ascending colon that was successfully resected with laparoscopic right hemicolectomy. PRESENTATION OF CASE: The patient is a 65-year-old man who developed hip joint pain and was diagnosed with polymyalgia rheumatica during the first year after laparoscopic right nephrectomy for right RCC. A screening colonoscopy was performed and a tumor was found in the ascending colon. Biopsy strongly suggested metastatic RCC. No other distant metastases were found, and laparoscopic right hemicolectomy was performed. The tumor extended from the mucosa to the subserosa and was diagnosed histopathologically as colonic metastasis of RCC. There were no lymph node metastases in the simultaneously resected mesentery, but venous invasion was observed. DISCUSSION: RCC can metastasize to various organs, but metastasis to the colon is extremely rare. In cases of colon metastasis, abdominal symptoms, hematochezia, or anemia may occur, and their occurrence should be checked during follow-up. Based on past reports, resection of metastatic lesion is considered the most appropriate treatment. CONCLUSION: Although it is rare for RCC to metastasize to the colon, it is possible. Resection can be recommended for colon metastasis with no other metastases, and colectomy with R0, including the regional mesocolon, may provide a favorable long-term prognosis.

[A Case of Laparoscopic Ileocecal Resection for Ascending Colon Cancer with Portosystemic Shunt].

A 72-year-old woman who underwent colorectal endoscopy because of positive fecal occult blood test results was diagnosed with ascending colon cancer.Preoperative CT revealed advanced ascending colon cancer and portosystemic shunt between the ileocecal vein and inferior vena cava.It was necessary to cut the shunt when ileocecal resection was performed. The patient had no symptoms caused by the shunt, and blood examination results showed no liver enzyme abnormalities. Abdominal ultrasound examination revealed no liver cirrhosis and normal blood flow in the portal vein and shunt flow from the ileocecal vein to the inferior vena cava.We assessed that surgery could be safely performed without increasing portal vein pressure.Laparoscopic ileocecal resection was performed by cutting the shunt.Partial jejunum resection was also performed for a mesenteric tumor observed intraoperatively, and pathological findings revealed a lymphangioma.The patient was discharged home on postoperative day 7 without any symptoms, liver enzyme abnormalities, or ascites suggestive of increased portal vein pressure on abdominal ultrasound examination.Colorectal cancer surgery with simultaneous cutting of a portosystemic shunt has rarely been reported.It is necessary to consider the causes of portosystemic shunt and then cut the shunt during surgery when needed.

Who needs diverting ileostomy following laparoscopic low anterior resection in rectal cancer patients? Analysis of 417 patients in a single institute.

BACKGROUND: Anastomotic leakage (AL) is one of the most serious complications after low anterior resection (LAR) for rectal cancer, and the significance of diverting stoma to prevent AL is still controversial. The aim of this study is to clarify the potential benefits and safety of diverting ileostomy (DI) following laparoscopic LAR in rectal cancer patients. METHODS: This was a retrospective cohort study of 417 rectal cancer patients who underwent laparoscopic LAR in a single institute. The risk factors for AL and the DI-related morbidity were assessed. RESULTS: DI was performed in 226 patients (54.2%). The incidence rates of symptomatic AL showed no significant difference between patients with and without DI (8.4% vs. 10.0%, p = 0.612). AL requiring a surgical intervention was relatively lower in patients with DI than in those without DI (1.8% vs. 4.7%, p = 0.097). DI construction was an independent risk factor for AL requiring a surgical intervention (OR 3.47, p = 0.041), as was the serum albumin level (p = 0.003), and being male was a relative risk factor (p = 0.058). Focusing on sex, the rate of AL requiring a surgical intervention was significantly different in male (1.7 and 7.9%, p = 0.021) but not in female patients (1.9 and 1.1%, p = 1.000) with and without DI. The DI construction-related morbidity was 9.7%, and no patient required a reoperation. Of 226 patients with DI, 209 (92.5%) underwent stoma closure 118 days (median 30-509 days) after LAR. The stoma closure-related morbidity was 9.1% and 1 patient (0.5%) required a reoperation due to anastomotic leakage. CONCLUSIONS: DI following laparoscopic LAR can decrease the risk of AL, requiring a surgical intervention, especially in male patients with malnutrition. However, due to DI-related morbidity, DI is not recommended in female patients.

Laparoscopic surgical management of a mature presacral teratoma: a case report.

BACKGROUND: Mature presacral (retrorectal) teratoma is very rare. We report a case in which a mature retrorectal teratoma in an adult was successfully treated with laparoscopic surgery. CASE PRESENTATION: A 44-year-old woman was diagnosed with a presacral tumor during a physical examination. Endoscopic ultrasonography (EUS) revealed a multilocular cystic lesion; the lesion was on the left side of the posterior rectum and measured approximately 30 mm in diameter on both contrast-enhanced pelvic computed tomography (CT) and magnetic resonance imaging (MRI). The presumptive diagnosis was tailgut cyst. However, the histopathological diagnosis after laparoscopic resection was mature teratoma. It is still difficult to preoperatively diagnose mature retrorectal teratomas. CONCLUSIONS: Laparoscopic resection of mature retrorectal teratomas is a feasible and promising method that is less invasive and can be adapted without extending the skin incision.

A successful case of laparoscopic colorectal cancer resection in an elderly patient with factor XI deficiency.

BACKGROUND: Congenital XI factor deficiency is a rare disease caused by autosomal recessive inheritance. Clinically, there are few spontaneous hemorrhages, which can cause abnormal bleeding after trauma, surgery, and tooth extraction. We experienced a colon cancer patient with congenital XI factor deficiency who was successfully treated by laparoscopic approach with the administration of the preoperative fresh frozen plasma (FFP). CASE PRESENTATION: The patient was an 82-year-old woman who complained of right lower abdominal pain for a period of 2 months with no previous history of abnormal hemostasis. She received colonoscopy and was diagnosed with ascending colon cancer. Preoperative blood tests resulted in prolongation of activated partial thromboplastin time (APTT). After further investigation, factor XI (FXI) activity was found to be abnormal at 3.0% and congenital FXI deficiency was diagnosed. By replenishing FXI by FFP, APTT was improved to 37 s so perioperative abnormal bleeding could be avoided and an operation for ascending colon cancer performed. The patient received laparoscopic ileocolic resection and was discharged on a postoperative day 7 uneventfully. CONCLUSION: It is important to detect coagulation disorders such as FXI deficiency during routine preoperative checkups, and it is also important to consider unrecognized coagulation disorders if we encounter unexplained abnormal bleeding after surgery or trauma. In patients who have already been diagnosed with FXI deficiency, appropriate treatment including administration of FFP should be considered before surgery, and laparoscopic approach has a possibility to bring safety outcomes as an effect of the reduction of the intraoperative bleeding.

Antistress effects of Kampo medicine "Yokukansan" via regulation of orexin secretion.

OBJECTIVE: Various stressors induce stress responses through the hypothalamic-pituitary-adrenal and the sympathetic-adrenal-medullary axes, which are regulated, in part, by orexin. For example, secretion of orexin in the hypothalamus is increased in rats exposed to the stress of social isolation for 1 week. In this study, the antistress effects of Kampo medicine Yokukansan (YKS) via the regulation of orexin secretion were investigated using a rat model. METHODS AND RESULTS: The administration of 300 mg/kg per day of YKS to rats for 1 week significantly decreased the plasma orexin levels compared with non-treated rats, whereas the administration of 1,000 mg/kg of YKS had no effect on orexin levels. Therefore, 300 mg/kg of YKS was an effective dose for controlling orexin secretion. Subsequently, rats were divided into group-housed control (Con), individually housed stress (Stress), and individually housed YKS (300 mg/kg)-treated stress (Stress + YKS) groups. After 1 week, a resident-intruder aggression test was performed, and the plasma levels of orexin and corticosterone were measured. In the Stress group, aggressive behavior and the levels of corticosterone and orexin significantly increased compared with the Con group; however, these effects were inhibited in the Stress + YKS group. Further, an orexin receptor antagonist (TCS 1102; 10 mg/kg) was intraperitoneally administered to rats exposed to isolation stress to determine whether orexin was involved in stress responses. Under these conditions, aggressive behavior and the level of corticosterone significantly decreased compared with the Stress group. CONCLUSION: These results suggest that orexin is involved in the control of stress response and that YKS exerts an antistress effect via the regulation of orexin secretion.

Efficacy of Juzentaihoto for Tumor Immunotherapy in B16 Melanoma Metastasis Model.

Introduction. Medical care for Japanese cancer patients includes Western and Kampo medicines, and treatments with juzentaihoto (JTT) reportedly prevent cancer metastasis and recurrence. In this study, we examined the effects of JTT on natural killer (NK) cell activity and metastasis in combined treatments with anti-PD-1 antibody in a mouse model of melanoma metastasis. Methods. C57BL/6 male mice were intravenously injected with B16 melanoma cells (B16 cell) and were given chow containing 3% JTT. In subsequent in vivo experiments, we assessed serum cytokine levels and tumor colony formation in the lungs. Additionally, we assessed NK cell activity in ex vivo experiments. Results. JTT significantly suppressed B16 cell metastasis, whereas injection of anti-asialo-GM1 antibody into mice abrogated the inhibitory actions of JTT. JTT significantly increased interleukin- (IL-) 12 and interferon- (IFN-) γ levels in serum and induced NK cell activity. It increased the inhibitory actions of the anti-PD-1 antibody on B16 cell metastasis. Discussion. These data suggest that JTT inhibits B16 cell metastasis by inducing NK cell activity. Additionally, combination therapy with JTT and anti-PD-1 antibody increased treatment response rates for B16 melanoma.

Influence of Periostin on Synoviocytes in Knee Osteoarthritis.

BACKGROUND: Periostin (POSTN) is a protein that binds to integrins to support adhesion and migration of epithelial cells. Mice lacking this gene exhibit cardiac valve disease as well as skeletal and dental defects. Recent studies indicated that periostin is involved in the pathogenesis and progression of knee osteoarthritis (OA). We investigated the influence of periostin and matrix metalloproteinases (MMPs) on OA synoviocytes. MATERIALS AND METHODS: OA patients were classified according to the Kellgren-Lawrence system and the levels of periostin, interleukin (IL)-4, IL-13 and transforming growth factor-ß (TGFß) in the synovial fluid were measured. MMPs or tissue inhibitor of MMPs (TIMPs) with periostin in cultured cells were measured when periostin was added to OA-associated synovial cells. Dexamethasone, a steroid medication which shows immunosuppressive effects, was used to investigate the influence of the downstream cascade. RESULTS: Periostin and IL-13 levels were up-regulated during the progression of OA. MMP-2 and MMP-3 levels increased in a periostin concentration-dependent manner. Increase in MMP-2 and MMP-3 levels was inhibited by dexamethasone treatment. CONCLUSION: In vivo results herein indicate that IL-13 may induce periostin production in OA. Furthermore, periostin may facilitate MMP production in OA-associated synovial cells.

Influence of IL13 on Periostin Secretion by Synoviocytes in Osteoarthritis.

BACKGROUND: Our previous research provided evidence of periostin increase in parallel with interleukin-13 (IL13) increase in the synovial fluid of patients with osteoarthritis (OA). The reaction cascade from IL13 to periostin, however, remains unidentified. We, therefore, tested the hypothesis that periostin secretion is affected downstream of IL13. MATERIALS AND METHODS: OA synoviocytes were cultured under different concentrations of IL13. Periostin content in culture supernatants and the level of signal transducer and activator of transcription 6 (STAT6) in the cultured cells were measured using enzyme-linked immunosorbent assay (ELISA). Moreover, the influence of dexamethasone and leflunomide on periostin production in relation to the effect of IL13 on the cells was also examined. RESULTS: Periostin content in culture supernatants and the level of STAT6 in cultured cells were significantly increased by IL13. The increase of periostin was significantly inhibited by dexamethasone and leflunomide. CONCLUSION: Periostin may be up-regulated in OA synoviocytes via STAT6 downstream of IL13.

Influence of Mechanical Force on Bone Matrix Proteins in Ovariectomised Mice and Osteoblast-like MC3T3-E1 Cells.

AIM: To investigate the effect of mechanical stress on periostin and semaphorin-3A expression in a murine model of postmenopausal osteoporosis and in osteoblast-like MC3T3-E1 cells. MATERIALS AND METHODS: Female mice were divided into three groups and treated with a sham operation, ovariectomy (OVX) or OVX plus treadmill training (OVX+Run). After 10 weeks, tibias were used for histological analysis. MC3T3-E1 cells were burdened by mechanical stress using a centrifuge or were treated with periostin, and the production of biologically-active semaphorin-3A was examined in vitro. RESULTS: In OVX+Run group tibias, the number of tartrate-resistant acid phosphatase-positive osteoclasts was lower than in the OVX group, and the expression of periostin and semaphorin-3A was higher. In MC3T3-E1 cells, centrifugal stress significantly increased periostin and semaphorin-3A mRNA expression. Treatment with periostin increased the semaphorin-3A level. CONCLUSION: We speculate that mechanical load may increase periostin production in osteoblasts, and periostin may inhibit osteoclast differentiation by its effects on semaphorin-3A. Our results support the concept of a positive correlation between exercise and inhibition of osteoclasts in post-menopausal osteoporosis.

Inductive Effect of Palmatine on Apoptosis in RAW 264.7 Cells.

Osteoporosis is a serious public health problem characterized by low bone density and deterioration of the bone microarchitecture. Current treatment options target either osteoclast resorption or osteoblast formation. It has been reported that berberine, a close structural analog of palmatine, inhibited bone loss in an osteoporosis model. In this study, osseous metabolism was observed in vitro with osteoclast bone resorbing cells. We proved that mouse preosteoclastic cell line (RAW 264.7) has a higher sensitivity to palmatine than mouse osteoblastic cell line (MC3T3-E1); the cell survival rates significantly decreased at 40 µM palmatine. The NO2 (-) level, a metabolic product of nitric monoxide (NO), and iNOS mRNA expression, an osteoclast with NO induced enzyme, also increased with higher dosage of palmatine. Furthermore, it was recognized that the cell viability decrease from palmatine was caused by apoptosis rather than necrosis. Additionally, osteoclast apoptosis from palmatine did not occur when iNOS was inhibited with N(G)-nitro-L-arginine methyl ester hydrochloride (pan NOS inhibitor). These results indicate that palmatine plays an important role in osteoclast apoptosis via the NOS system. Hence, palmatine could be considered as a viable pharmaceutical candidate for osteoporosis bone resorption inhibitor.

Influence of Palmatine on Bone Metabolism in Ovariectomized Mice and Cytokine Secretion of Osteoblasts.

BACKGROUND/AIM: Receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG), regulate the cognate receptor RANK on osteoclast precursor cells. Herein we examined the inhibitory effects of palmatine on bone metabolism using ovariectomized (OVX) mice. MATERIALS AND METHODS: The first experimentaI set was designed to histologically and biochemically examine mice randomly divided into four groups: sham-operated, OVX, and OVX-palmatine intake groups (1 mg/kg and 10 mg/kg). The second experimental set examined the influence of palmatine on osteoblast-like cells in vitro. RESULTS: Palmatine caused significant suppression of osteoclast numbers in tissues. In palmatine-treated mice, RANKL and OPG expression decreased. In the culture supernatant of MC3T3-E1 cells, RANKL and OPG levels were significantly reduced by palmatine addition. CONCLUSION: Palmatine may attenuate osteoclast differentiation through inhibition of RANKL and OPG expression by osteoblasts. Therefore, palmatine might be a candidate anti-resorptive agent for osteoporosis therapy.